Adenoviruses have been widely used as vectors for the transfer of
genes. In
spite of one highly publicized death in a gene therapy trial,
excellent safety precedents exist. Adenovirus-based vaccines have
been used in humans for 30 years, vaccinating all US military
recruits, without any serious side effects.
First generation adenovectors
presently in the clinic and in research laboratories are providing
the knowledge base for the development of improved systems for gene
transfer and drug delivery. First generation adenovectors have been
used to dose thousands of patients in clinical trials and two
vectors have already been approved in China for the treatment of
solid tumors.
The major advantages of adenovectors are:
• large amounts of vectors can be produced
• ability to transduce both fast and slow growing cells
• ability to transduce a wide variety of cell types
• ability to accommodate large fragments of foreign genetic material
However, first generation vectors have limitations as well. These include:
• lack of sustained expression
• lack of efficiency in some clinically relevant cancer cells
• possible toxicity at high doses due to absence of cell and tissue specificity
• inability to multiple dose because of the human body’s defense reactions against
the vector
VectorLogics has developed four major technologies to achieve fundamental improvements and address major hurdles in adenovector-based biological drug delivery. These improvements are in:
• targeting efficiency
• targeting specificity
• cell and tissue selectivity
• shielding
The adenovectors developed by VLI constitute a major paradigm shift in the development of next generation vectors, compared to vectors used in the clinic today. VLI has developed innovative technologies that modify the adenovector outer coat proteins to significantly increase their effectiveness. These technologies can be applied to different treatment modalities or can be combined in a single vector for maximum efficacy and safety.
Efficiency: Increased Transduction
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VLI has developed technology to modify the adenovector outer coat proteins for the increased transduction of tumor cells. Efficiency of transduction is a major determinant of the eventual effectiveness of a vector for clinical use. VLI's lead product is a transduction-enhanced, conditionally replicative adenovector
(CRAd) to treat solid tumors. This vector can effectively destroy solid tumors, largely because it can deliver its payload to cancer cells much more effectively than unmodified first generation adenovectors used previously in clinical trials. This means that VLI's transduction enhanced vectors can be used to treat cancers such as ovarian, pancreatic, colorectal and prostate, which have not been effectively treatable with first generation adenovectors.
Selectivity: Selective Transduction
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VLI has developed technology to modify the adenovector outer coat proteins for the selective transduction of immune and tumor cells for increased efficacy and safety. This type of molecular targeting is achieved through adding ligands to the vector that recognize tissue- or disease-specific receptors selectively expressed on the target cells. The effective transduction of immune cells increases vaccine immunogenicity with a corresponding increase in protection against the specific diseases. Such molecular targeting strategies could be used for the treatment of disseminated diseases such as cancer metastasis. VLI is developing products that specifically target dendritic cells for effective cancer vaccine therapeutics.
Safety: Cell and Tissue Specificity
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Specific modifications to the
adenovector genes allows for the recognition of the status of a specific cell
type. Since most aggressive cancers carry specific mutations, adenovectors with
these types of genetic elements can recognize cancerous tissue. VectorLogics’
lead product is a transduction-enhanced, conditionally replicative adenovector
that is able to discriminate between cancer specific and normal cells for a more
effective cancer treatment with fewer side effects. The incorporation of
cancer-specific genetic entities enables VLI product candidates to be highly
specific to cancer and so reduce toxicity and damage to healthy tissue. These
features clearly distinguish the vector approach from a traditional cytotoxic
therapy.
Shielding: Multiple-Dosing
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Shielding of adenovectors is being
developed to solve a serious problem encountered in major clinical
trials. There is an immense medical need for drug re-dosing.
Re-dosing is possible with small molecule based drugs, but
relatively difficult with biologicals and first-generation vectors.
The problem has not been solved for adenovectors presently in
several major clinical trials. The ability to re-dose a patient with
an adenovector allows for the use of this system for standard
immunization strategies and additionally solves the problem of both
cancer and prophylactic vaccination with biological vectors.
Furthermore, it solves the problem of immune extinguishments of
conditionally replicative vectors, boosting their usefulness and
functionality by increasing their persistence and therapeutic
benefits. Simply stated, shielding produces “stealth” vectors to be
able to deliver therapeutical agents multiple times. These vectors
will destroy cancer cells without being detected by the human immune
system.
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VectorLogics' Core Technologies and
Applications
VectorLogics has an intellectual
property portfolio that includes 21 issued or allowed US and foreign
patents serving as the foundation for the development of its
molecular medicines. Molecularly targeted vectors can solve the
problem of delivering and maintaining therapeutic levels of protein
at the site of disease. Not unlike medicinal chemistry that modifies
small chemical moieties for drug development, VLI uses “Medicinal
Biology” to modify the adenovectors for increased efficiency and
safety. These technologies can be applied to different treatment
modalities or can be combined in a single vector for maximum
efficacy.
Relevant
Publications
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Hedley, S.J., Chen,
J., Mountz, J.D., Li, J., Curiel, D.T., Korokhov, N., and Kovesdi,
I. (2006) Targeted and Shielded Adenovectors for Cancer Therapy.
Cancer Immunol. Immunother. 55, 1412-1419.
